PROJECT SUMMARY The purpose of this K01 Mentored Research Scientist Development Award is to promote Dr. Lindsey Lepley?s independent research program by training under Dr. David Goldhamer and other skilled musculoskeletal physiologists, orthopaedic surgeons, statisticians and engineers at the University of Connecticut, to gain the necessary scientific skills and career development to advance her research line to a new level. Dr. Lepley?s long-term career goal is to lead a research team focused on developing evidence-based strategies to prevent the development of post-traumatic osteoarthritis (PTOA). The training provided by this K01 would provide her with the needed support to become a productive independent scientist who is able to measure the inflammatory, neural, and morphological responses of muscle and alterations in bone and cartilage health to traumatic joint injury and subsequent rehabilitation strategies. The central tenant of this K01 is to identify rehabilitation strategies capable of promoting muscle and joint health after anterior cruciate ligament (ACL) injury. To date, concentric exercise is the standard mode of exercise prescription after ACL injury. Yet, multiple systematic reviews have shown that concentric exercise does not restore muscle strength and does not deter the onset of PTOA. Emerging evidence suggests that mechanical stress achieved via eccentric exercise is required to initiate strain-sensing molecules that promote the recovery of muscle. We have recently demonstrated that embedding eccentric exercise into a rehabilitation program early after ACL reconstruction promotes the recovery of quadriceps strength better than concentric exercise. Though promising, eccentric exercise is often avoided clinically, as the notion that eccentric exercise is associated with muscle injury has been perpetuated in the literature, and the underlying benefits of eccentrics to muscle remain undefined. Further, the ability of eccentric exercise to prevent the development of PTOA in a high-risk population has never been studied. To provide the evidence-based data needed to support the incorporation of eccentric exercise into rehabilitation, we will establish a non-invasive, clinically-translatable, ACL injury in a rat model and describe the time course of biomechanical alterations, inflammatory response and PTOA progression (aim 1). We will then use this model to report the effectiveness of eccentric exercise to treat muscle weakness (aim 2) and promote bone and cartilage health after ACL injury (aim 3). The central hypothesis is that eccentric exercise will attenuate deficits in neural activity and alterations in muscle morphology, thereby restoring quadriceps strength and promoting joint health more effectively than the current standard of care of concentric exercise after ACL injury. The rationale for conducting this in vivo research, which establishes the physiological benefits of this rehabilitation strategy, is to ultimately inform the development of future clinical trials and generate essential new skills that will promote Dr. Lepley?s independent research program.